Separations of all types are routinely done by the exploitation of physical and chemical differences in the various species to be separated. Size exclusion, boiling point, and chemical affinity are techniques that have been used for separations of particles, chemical species, and biological moieties for hundreds of years. More recently, the use of magnetism has been used as a tool for separation of various species material from one another. By the early 1960's, the first stable magnetic fluid colloid had been described. Later research led to the development of a separations device based on magnetic density gradients in magnetic fluid columns. By 1979, magnetic particles coated with appropriate functional chemical groups for affinity chromatography separations were reported. The first commercial application of magnetic separations was described by Chagnon et al in U.S. Pat. No. 4,628,037. The Chagnon patent describes the use of amine terminated silane coupled magnetic particles for immunodiagnostic applications. The materials described in the Chagnon et al patent are now used commercially in medical diagnostic kits.
Magnetic separations have not been exclusively applied to in vitro applications. The use of magnetic separations for in vivo applications is becoming increasingly more accepted and important as a therapeutic and diagnostic tool. By the early 1980's, published reports described the magnetic targeting and isolation of chemotherapeutic drugs into rat-tail sarcoma. Widder (U.S. Pat. Nos. 4,849,210; 4,247,406; and 4,230,685) describe the use of magnetic albumin spheres for ultrasound contrast media and magnetic drug targeting. Schroeder (U.S. Pat. No. 4,501,726) reports a method of preparing magnetic starch beads for use in MRI imaging for the separation of T.sub.1 /T.sub.2 relaxation signals.
In all of this previous work, the use of magnetic separations has been done on magnetic particles of varying particle size distribution. The magnetic particle is coated with an organic compound, and used either as a signal (e.g., MRI), targeting agent (e.g. in drug delivery) or for separation in a magnetic field (e.g. in vitro separations). However, an advantage in enhanced separations, for example, could be achieved if the magnetic particle could alter its size, shape or magnetic properties while in use in a controlled fashion.
Various methods have been reported for preparing inorganic or inorganic oxide particles of some degree of particle size control:
U.S. Pat. No. 5,071,076 describes a method for producing magnetic microparticles from metallocenes. The method involves combining an aqueous slurry of the metallocene and an aqueous slurry of a metal hydroxide and milling the slurries together.
U.S. Pat. No. 4,987,012 describes a process for preparing spherical particles of hydroxide having a particle diameter from 0.1 to 10 .mu.m by adding a corresponding metal alkoxide to a dispersion of a water-alcohol system having dispersed therein a metal oxide or hydroxide as a seed, under alkaline conditions and allowing a decomposition product from said metal alkoxide to attach onto said seed to effect particle growth of the seed. The improvement reported comprises maintaining said dispersion at a substantially constant pH within the range between 10 and 13 during the addition of the metal alkoxide to said dispersion and the subsequent particle growth of the seed, thereby to prepare mono-dispersed particles substantially free from particle aggregation having a sharp particle size distribution of a standard deviation of not greater than 0.5.
U.S. Pat. No. 4,985,273 describes a method of producing fine inorganic particles. The method comprises the steps of reacting an inorganic fine particle on the entire surface thereof with a silane type surface active agent containing a straight hydrocarbon chain and a functional group to form a monomolecular film on the entire surface of said inorganic fine particle, thereafter making the inorganic fine particles covered with the monomolecular film in a predetermined density on a substrate, and thereafter subjecting the monomolecular film to physical or chemical treatment to allow the functional groups to be chemically bonded to each other.
U.S. Pat. No. 4,945,049, reports on a method for preparing magnetic powder comprising homogeneous and fine particles using an alkali-producing enzyme. Particles having a particle size ranging from 50 to 500 nm's were reported.
U.S. Pat. No. 4,702,775 describes the control of particle size in the preparation of magnetite pigments. The mean particle size was brought to a value within the range of 0.06 to 0.5 .mu.m by means of a residence stage between the precipitation stage and the oxidation stage.
Various other disclosures describe the preparation of microporous membranes, primarily for a filtration purpose, which limit the passage of selected size molecules within a particular liquid medium. For example, U.S. Pat. No. 4,943,374 concerns the use of a microporous membrane constructed of a polyether sulfone and hydrophilization agent having a pore size which is within the range of 0.1 and 1.2 microns for the filtration of beer. U.S. Pat. No. 4,954,381 describes the preparation of porous substrates having well defined morphology. U.S. Pat. No. 4,964,992 describes a membrane filter having predetermined controlled porosity and to the method for making such a membrane filter. U.S. Pat. No. 5,057,226 describes a method of removing a constituent of a biological fluid including a blood component, said method including flowing the biological fluid past one side of a first semipermeable membrane, flowing solution containing a first precipitation agent past a second side of the membrane so as to cause transfer of the precipitation agent through the membrane to the biological fluid so as to improve precipitation characteristics of the fluid; and precipitating the constituent.
What emerges from the above, therefore, is the lack of a convenient method to control inorganic oxide particle size, such that particle size control can then be further utilized to manufacture novel aggregate particle clusters with unique chemical or physical-chemical properties.
Accordingly, it is an object of this invention to provide a method for producing inorganic oxides of substantially uniform particle size, coating said particles with various functional moieties, and clustering said moieties together via controllably degradable chemical, complex or ionic bonds.
It is also an object of this invention to provide a method of producing magnetic particle or organic coated particle beads, linking said particle or particle beads together to form a large aggregate cluster with different chemical, physical, or magnetic properties than the unit particle or bead from which it is derived, and controllably and predictably revising the cluster back to unit bead or particle, and vice versa.
It is also a further object of this invention to provide a method of producing unit magnetic crystals of small, substantially uniform particle size for use in preparing magnetic-molecular switches and apply such to several in vitro and in vivo medical and biological applications.